Abiraterone acetate, the chemical name of which is (3β)-17-(3-pyridinyl) androsta-5,16-dien-3-yl acetate, is the prodrug of the active metabolite abiraterone, a selective inhibitor of the enzyme CYP17.
Abiraterone acetate is the active ingredient of a novel medicament for the treatment of prostate carcinoma in adult men.
The preparation of abiraterone acetate was originally disclosed in EP0633893.
The synthesis scheme involves the conversion of dehydroepiandrosterone-3-acetate (I) to the corresponding enol triflate (II) by treatment with trifluoromethanesulphonic anhydride and 2,6-di-tert-butyl-4-methylpyridine.
The Suzuki reaction between 3β-acetoxyandrosta-5,16-dien-17-yl trifluoromethanesulphonate (II) and diethyl(3-pyridyl)borane affords crude abiraterone acetate which is purified by silica gel chromatography, eluting with a mixture of ethyl ether and petroleum ether, and finally crystallised from hexane.

The crude abiraterone acetate obtained under said conditions contains substantial amounts of the following impurity (IV), deriving from the elimination of acetic acid in the presence of 2,6-di-tert-butyl-4-methylpyridine [Journal of Medicinal Chemistry 38, 2463-2471 (1995)]

The use of more common, cheaper bases of 2,6-di-tert-butyl-4-methylpyridine is claimed in patent application WO2006/021777 (see also EP1781683 and U.S. Pat. No. 8,236,946); above all the formation of impurity IV is avoided by using said bases, although the intermediate II formation reaction is not complete, and the crude abiraterone acetate obtained after the Suzuki reaction contains appreciable amounts of dehydroepiandrosterone-3-acetate (I). Said crude product can be purified by salification of III with methanesulphonic acid (WO2006/021776, see also EP1789432 and U.S. Pat. No. 8,076,474); however, the purity of the mesylate thus obtained is not very high, even after recrystallisation from isopropyl alcohol (purity of crude product <90%, purity of purified product about 96%), and the overall yield is rather poor.
A sequence comprising purification of crude product III via formation of the salt with sulphuric acid, reconversion to III and final crystallisations from dichloromethane/petroleum ether and ethanol/water, is disclosed in IPCOM000211139D. The yields and quality of the products obtained are not reported, and treatment with acetic anhydride/DMAP is performed before the final crystallisations.
An alternative process for the preparation of abiraterone acetate is disclosed in EP0721461.

The key intermediate of this process is 17-iodo-androsta-5,16-dien-3β-ol VII, obtained in two steps from dehydroepiandrosterone V via hydrazone VI. The Suzuki reaction between vinyl iodide VII and diethyl(3-pyridyl)borane affords abiraterone VIII, which is then acetylated to give abiraterone acetate III.
The process is described in detail in Organic Preparations and Procedures International 29, 123-128 (1997).
As in the case of the synthesis process illustrated in the previous scheme, this process also requires an elaborate procedure for the purification of crude abiraterone acetate, which comprises (see the publication cited above) one direct-phase (silica) chromatography step and one reverse-phase (LiChroprep® RP-8) chromatography step, together with repeated crystallisations from organic solvents. This elaborate purification procedure is mainly required to remove a critical impurity that forms during synthesis of VIII by Heck-type reaction between VII and VIII, to give “dimer” IX after acetylation.

All said chromatography procedures are unsuitable for use to produce abiraterone acetate on an industrial scale.
If the purification processes described in the prior art were applied, it would be very difficult to eliminate the impurities present completely; moreover, the procedures are laborious, and losses are very high.